ABSTRACT Each year, over half a million head and neck cancer patients are treated with radiotherapy, which results in the severe dry mouth syndrome, xerostomia, due to co-radiation of healthy salivary glands. Poor quality of life in such patients is a result of conditions associated with xerostomia such as hyposalivation, dental caries, fungal infections, decaying teeth, and taste and masticatory dysfunctions. Current therapies to rescue hyposalivation provide temporary relief and are largely ineffective; thus, new therapies for permanent tissue repair are needed. Our lab has deep expertise in cutting-edge salivary glands stem cell research, and was the first to demonstrate the clinical potential of KIT+ (c-Kit, CD117) stem/progenitor cells in rescuing hyposalivation. However, this population of stem/progenitor cells decreases with age, currently compromising our ability to efficiently use these cells for therapy. Our current work shows that transcription factor SOX10 plays a major role in the proliferation and differentiation potential of KIT+ cells. For example, epithelial depletion of Sox10 results in loss of KIT+ and pro-acinar cells in the fetal stages. However, it is unclear whether SOX10 is required for expansion and multi-potency, i.e. the ability to differentiate into all epithelial cell types, of KIT+ cells through adulthood. Based on existing evidence, we hypothesize that SOX10 plays a central role in the expansion and differentiation of all KIT+ cells. To test this hypothesis, we will lineage trace epithelial KIT+SOX10+ cells in the submandibular gland using inducible mouse systems. We will also assess forced overexpression of SOX10 to expand KIT+ cells. Overall, these studies will elucidate whether SOX10 marks multi-potent KIT+ stem cells, and can be applied to expand KIT+ stem cells. The scientific ideas proposed here will expand our knowledge of salivary gland stem cells, and will significantly improve future hyposalivation rescue stem cell-based therapies.